The river drains 27,500 square miles (71,000 km2), including nearly half of the land area of Pennsylvania. The drainage basin (watershed) includes portions of the Allegheny Plateau region of the Appalachian Mountains, cutting through a succession of water gaps in a broad zigzag course to flow across the rural heartland of southeastern Pennsylvania and northeastern Maryland in the lateral near-parallel array of mountain ridges. The river empties into the northern end of the Chesapeake Bay at Havre de Grace, Maryland, providing half of the Bay's freshwater inflow. The Chesapeake Bay is the ria of the Susquehanna.

The origin of the West Branch is near Northern Cambria, Pennsylvania. It travels northeasterly through Curwensville (where the river is dammed to form a lake), through Clearfield, Pennsylvania. The West Branch turns to the southeast and passes through Lock Haven and Williamsport before turning south. The North Branch joins the West Branch from the northwest at Northumberland, just above Sunbury.

"Susquehanna" comes from the Len'api (or Delaware Indian) term Sisa'we'hak'hanna, which means "Oyster River."[10] This mighty river has two branches that come together at Sakima'ing (modern Sunbury, Northumberland County), and flows south past Harrisburg to Havre de Grace, Maryland, and into the Chesapeake Bay. Oyster beds were widespread in the bay, which the Lenape knew.

The Len'api referred to the people at Con'esto'ga ("Roof-place" or "town," modern Washington Boro, Lancaster County), also called Ka'ot'sch'ie'ra ("Place-crawfish," modern Chickisalunga, Lancaster County), or Gasch'guch'sa ("Great-fall-in-river," modern Conewago Falls, Lancaster County)[11] as either Minquas ("quite different"), Mengwe ("without penis"), or Sisa'we'hak'hanna'lenno'wak ("Oyster-river-people").[12] The Len'api also called the area Sisa'we'hak'hanna'unk ("Oyster-river-place").

Along the Atlantic Coast, Native Americans were grouped among those coastal peoples who spoke the Algonquian languages, such as the Len'api (whose bands spoke three dialects of Lenape) and interior, Iroquoian languages-speaking peoples, such as the Eroni and the Five Nations of the Iroquois.[13] The English of Pennsylvania referred to the Eroni (people) of Conestoga as "Susquehannocks" or "Susquehannock Indians," a name derived from the Lenape term.[13] In addition, John Smith of Jamestown labeled their settlement as "Sasquesahanough" on his 1612 map when he explored the upper Chesapeake Bay area.[14]

In the 1670s the Conestoga, or Susquehannock, succumbed to Iroquois conquest by the powerful Five Nations based in present-day New York, and assimilated with them. In the aftermath, the Iroquois resettled some of the semi-tributary Lenape in this area, as it was near the western boundary of the Lenape's former territory, known as Lenapehoking.

In 1779 during the Revolutionary War, General James Clinton led an expedition down the Susquehanna from its headwaters. His party had made the upper portion navigable by damming the river's source at Otsego Lake, allowing the lake's level to rise and then destroying the dam and flooding the river for miles downstream. This event is described by James Fenimore Cooper in the introduction to his novel, The Pioneers.

At Athens, Pennsylvania, then known as Tioga or "Tioga Point", Clinton met with General John Sullivan and his forces, who had marched from Easton, Pennsylvania. Together on August 29, they defeated the Tories and warriors of allied Iroquois bands at the Battle of Newtown (near present-day Elmira, New York). This was part of what was known as the "Sullivan-Clinton Campaign" or the "Sullivan Expedition". They swept through western New York, destroying more than 40 Iroquois villages, as well as their stores of crops set aside for winter. Many of the Iroquois went to Canada as refugees; casualties from exposure and starvation were high that winter.

Pennsylvania and Connecticut both claimed land from the colonial era in the Wyoming Valley along the Susquehanna. Connecticut founded Westmoreland County here and defended its claim in the Pennamite Wars. Under federal arbitration, eventually the state ceded this territory to Pennsylvania.

In 1833, John B. Jervis began a canal system to extend the Chenango River and connect the waters of the Susquehanna from Chenango Point to the Erie Canal, which ran through the Mohawk Valley of New York, ultimately connecting with Lake Erie through the Wood Canal. In October 1836, water from the Susquehanna was connected to the Erie Canal at Utica, New York. Water travel was popular during that era, and the Erie Canal dramatically expanded trade between communities around the Great Lakes and markets in New York and Pennsylvania. With the expansion of construction of railroad lines, canal-transport became unprofitable, as it could not compete in speed or flexibility.[16] Boats had to climb a net height of 1,009 feet between basins, requiring the use of more than 100 water locks, which were too expensive to be maintained under the new competition.[16]

In 1972, the remnants of Hurricane Agnes stalled over the New York-Pennsylvania border, dropping as much as 20 inches (510 mm) of rain on the hilly lands. Much of that precipitation was received into the Susquehanna from its western tributaries, and the valley suffered disastrous flooding. Wilkes-Barre, Pennsylvania, was among the hardest-hit communities and the capital Harrisburg was flooded. The Chesapeake Bay received so much fresh water that it altered the ecosystem, killing much of the marine life that depended on saltwater.

In June 2006, portions of the river system were affected by the Mid-Atlantic Flood of June 2006, a flood caused by a stalled jet stream-driven storm system. The worst affected area was Binghamton, New York, where record-setting flood levels forced the evacuation of thousands of residents.

In March 2011, Crary Park in Shickshinny, Pennsylvania was inundated with a flood when the Susquehanna at Wilkes-Barre rose above 27 feet.[18] Six months later, the town was devastated by a 42-foot record flood.[19]

In September 2011, the Susquehanna River and its communities suffered some of the worst flooding since Agnes in 1972.

The Susquehanna River has played an important role in the transportation history of the United States. Prior to the 1818 opening of the Port Deposit Bridge, the river formed a barrier between the northern and southern states, as it could be crossed only by ferry. The earliest dams were constructed to support ferry operations in low water. The presence of many rapids in the river meant that while commercial traffic could navigate down the river in the high waters of the spring thaws, nothing could move up. Two different canal systems were constructed on the lower Susquehanna to bypass the rapids. The first was the Susquehanna Canal, also called the Conowingo Canal or the Port Deposit Canal, completed in 1802 by a Maryland company known as the Proprietors of the Susquehanna Canal. The second was the much longer and more successful Susquehanna and Tidewater Canal. The canals required additional dams to provide canal water and navigation pools.

As the industrial age progressed, bridges replaced ferries, and railroads replaced canals. The railroads were often constructed on top of the canal right-of-way along the river. Many canal remnants can be seen in Havre de Grace, Maryland, along US Route 15 in Pennsylvania, and in upstate New York at various locations. These latter remnants are parts of the upstream divisions of the Pennsylvania Canal, of privately funded canals, and of canals in the New York system.

Satellite photo of the Susquehanna (upper left) where it empties into the Chesapeake Bay (center)

The environmental group American Rivers named the Susquehanna "America's Most Endangered River for 2005" because of the excessive pollution it receives. Most of the pollution in the river is caused by excess animal manure from farming, agricultural runoff, urban and suburban stormwater runoff, and raw or inadequately treated sewage. In 2003 the river contributed 44% of the nitrogen, 21% of the phosphorus, and 21% of the sediment flowing into the Chesapeake Bay.[20] It was designated as one of the American Heritage Rivers in 1997.[21] The designation provides for technical assistance from federal agencies to state and local governments working in the Susquehanna watershed.

The Susquehanna River has long been associated with boating because of its many migratory fish. Many tourists and local residents use the Susquehanna in the summer for recreation purposes such as kayaking, canoeing, and motor-boating. Canoe races are held annually on various sections of the river, such as the amateur race held in Oneonta, New York.

Susquehanna rowing and paddling have a long history. Starting in 1874, rowers from Shamokin Dam, Pennsylvania raced men from Sunbury. The General Clinton Canoe Regatta, a 63-mile (claimed 70) flat-water race, takes place each year in Bainbridge, New York on Memorial Day weekend. Binghamton University Crew and Hiawatha Island Boat Club are also located on the river, in the Southern Tier of New York.